HIGHLY SELECTIVE, NOVEL ANALOGS OF 4-[2-(DIPHENYLMETHOXY)ETHYL]-1-BENZYLPIPERIDINE FOR THE DOPAMINE TRANSPORTER - EFFECT OF DIFFERENT AROMATIC SUBSTITUTIONS ON THEIR AFFINITY AND SELECTIVITY
Ak. Dutta et al., HIGHLY SELECTIVE, NOVEL ANALOGS OF 4-[2-(DIPHENYLMETHOXY)ETHYL]-1-BENZYLPIPERIDINE FOR THE DOPAMINE TRANSPORTER - EFFECT OF DIFFERENT AROMATIC SUBSTITUTIONS ON THEIR AFFINITY AND SELECTIVITY, Journal of medicinal chemistry, 40(1), 1997, pp. 35-43
Several analogs of the potent and selective dopamine transporter (DAT)
ligand 4-[2-(diphenylmethoxy)ethy1]-1-benzylpiperidine, 1a, were prep
ared and biologically evaluated at the dopamine and serotonin transpor
ter (SERT) sites. Several substituents were introduced in the aromatic
rings to evaluate the influences of electronic and steric interaction
s in their binding to the DAT. All the novel analogs showed preferenti
al interaction at the DAT compared with the SERT. Different aromatic s
ubstitutions in the phenyl ring of the N-benzyl part of the molecule p
layed a key role in the selectivity. In general, compounds with strong
electron-withdrawing substituents were most active and selective at t
he DAT. Thus, compounds 5a (R = F) and 11b (R = NO2) were among the mo
st potent (IC50 = 17.2 and 16.4 nM, respectively) and most selective (
SERT/DAT = 112 and 108, respectively) and were far more selective than
GBR 12909 (SERT/DAT = 6). Bioisosteric replacement of one of the phen
yl rings of the diphenylmethoxy moiety by a thiophene ring was tolerat
ed well and produced the most potent compound 13b (IC50 = 13.8 nM) in
the series. Our current structure-activity studies of these piperidine
analogs resulted in the generation of second generation of GBR-type c
ompounds, and all of these new compounds reported here were more selec
tive than GBR 12909 in interacting with the DAT over the SERT.